Anger in Parkinson’s Disease: A Case-Control Study

Yolanda Macıas, PhD,1 Julian Benito-Leon MD, PhD,2 Elan D. Louis MD, MSc,3,4

and Antonio Cano-Vindel, PhD5

1Parkinson’s Disease Association of Mostoles, Mostoles, Madrid, Spain2Department of Neurology, University Hospital, “12 de Octubre”, Madrid, Spain

3Department of Neurology, G.H. Sergievsky Center, Taub Institute for Research on Alzheimer’s Disease and the Aging Brain,College of Physicians and Surgeons, Columbia University, New York, USA

4Department of Epidemiology, Mailman School of Public Health, Columbia University, New York, USA5Department of Psychology, Complutense University of Madrid, Madrid, Spain

Abstract: Cognitive-psychiatric features of Parkinson’s dis-ease (PD) are common and they may be as disabling as themotor features of the disease. PD has been associated with stoicand inflexible personality traits. While many features of per-sonality have been studied in PD, a systematic study of angertrait and anger expression in PD has not been performed. Weused the Spanish adapted version of the state–trait anger Ex-pression Inventory-2 (STAXI-2), comprised of six scales andan anger expression index, to measure anger trait and angerexpression. There were 126 PD patients with depressive symp-toms and 126 age- and gender-matched controls. PD patientshad lower levels of state anger (15.8 � 3.1 vs. 17.9 � 5.3, P �0.001), trait anger (19.2 � 5.3 vs. 20.7 � 6.0, P � 0.05), anger

expression-out (9.0 � 2.5 vs. 10.5 � 3.0, P � 0.001), andanger expression index (26.1 � 8.8 vs. 29.6 � 9.4, P � 0.002);and higher levels in anger expression-in (14.0 � 3.4 vs. 12.2 �3.2, P � 0.001), anger control-out (18.6 � 5.0 vs. 16.1 � 5.0,P � 0.001), and anger control-in (14.3 � 4.7 vs. 13.0 � 4.5,P � 0.05) than controls. These differences persisted in analysesadjusting for age, gender, and depressive symptoms. Conclu-sions: PD patients showed lower levels of external expressionof anger and higher levels of control of anger. Our resultsdemonstrate another dimension to the stoic personality traitseen in PD. © 2007 Movement Disorder Society

Key words: Parkinson’s disease; non-motor features;psychiatric.

Cognitive-psychiatric features of Parkinson’s disease(PD) are common and they may be as disabling as themotor features of the disease.1 For nearly a century, it hasbeen suggested that PD may be associated with a pre-morbid personality.2,3 This premorbid personality, inwhich stoic and inflexible traits are common, consists oftraits such as industriousness, punctuality, cautiousness,and lack of novelty seeking. The existence of this per-sonality is supported by case reports, twin studies, andcase-control studies.2-4

Although anger is a common human emotion, it hasnever been systematically studied in PD. In the literature,the term anger refers to the unpleasant emotional state

ranging in intensity from mild irritation or annoyance torage and fury, usually in response to perceived mistreat-ment or provocation.5-7 State anger is a transitory emo-tional phase whereas the predisposition for frequent,intense, long-lasting anger is a stable personality at-tribute known as trait anger. Anger reflects a phenome-non composed of internalized anger, externalized anger,and anger control. Internalized anger (anger-in) reflectsthe tendency to suppress angry feelings. In contrast,externalized anger (anger-out) reflects the tendency toengage in aggressive behavior toward objects or individ-uals in the environment. Finally, anger-control refers tothe ability to monitor and prevent the experience ofanger.5-7

The biological basis of anger is not fully known.Serotonin, and perhaps serotonergic dysregulation, maybe involved in the modulation of anger and aggressivebehavior.8-11 The serotonergic neurotransmitter system isinvolved in PD, although its exact role is unclear.12

*Correspondence to: Dr. Julian Benito-Leon, Avda. de la Constitu-cion 73, portal 3, 7° Izquierda, E-28821 Coslada, Madrid, Spain.E-mail: jbenitol@meditex.es

Received 12 July 2007; Revised 17 August 2007; Accepted 8 Sep-tember 2007

Published online 28 November 2007 in Wiley InterScience (www.interscience.wiley.com).

Movement DisordersVol. 23, No. 2, 2008, pp. 195–199© 2007 Movement Disorder Society

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Given these observations, we hypothesized that modula-tion of anger might be affected in PD, and more specif-ically, that PD patients might tend to repress feelingssuch as anger. We therefore conducted a case-controlstudy of anger in PD, using the Spanish adapted versionof the State–Trait Anger Expression Inventory-2(STAXI-2).13,14 The goal of the study was to determinewhether patients with PD differ from controls in any ofthe six scales and the anger expression index of thisinstrument.

PATIENTS AND METHODS

General Study Design

Our sample of PD patients was derived from sevenSpanish PD associations. These PD associations weresituated in seven cities throughout Spain (Madrid city,Mostoles, Villarrobledo and La Roda in Central Spain;Sevilla in Southern Spain; Castellon in Northeast Spain;and Salamanca in Norwestern Spain), thereby represent-ing a broad geographic sampling. The associations werechosen according to the following criteria: (1) there wasa close relationship between our research group and eachof these associations, and (2) each association main-tained a computer-based registry of PD patients. In thesecomputer-based registries, basic demographic data of themembers (e.g., age and gender) were recorded. We ob-tained permission in each association to access this con-fidential information. Five of the seven associations in-cluded 40 to 100 patients with PD whereas in Sevilla andMadrid, there were more than 1,000 patients with PD.Within each registry, we recruited patients with PD with-out regard to age or gender or other demographic factors(i.e., every nth name was selected from patient lists so asto achieve the needed number of recruits). Controls wererecruited from each of the seven cities from which pa-tients with PD were chosen. They were similarly selected(every nth name was selected so as to achieve the needednumber of recruits) from the records of local associationsof retired individuals in the same neighborhood as thePD association. Each control was free of known neuro-logical. None of the control subjects had symptoms or ahistory of a neurological disorder (e.g., parkinsoniandisorders and cognitive impairment) and none had re-ceived a neurological diagnosis from a physician.

Eligibility Criteria

Patients aged 18 and older, were included in the studyif they had met the United Kingdom Parkinson’s DiseaseSociety Brain Bank criteria.15 Patients excluded from thestudy were those (1) institutionalized at the time ofobservation, (2) who had major acute comorbidities or

any major serious chronic illness 3 months before inclu-sion (patients with a stable chronic medical conditionwere included), and (3) patients with any neurologicalillness other than PD, including dementia. A senior neu-ropsychologist (Y.M.), specializing in cognitive prob-lems associated with PD, performed a mental statusexamination on each patient and control, applying theDSM-IV criteria16 and excluded those individuals whohad dementia. Also excluded were those individuals withvisual hallucinations or psychosis and those who couldnot complete the neuropsychological evaluations.

Enrolment and Clinical Variables

The study was approved by the Ethical Committee ofthe Mostoles General Hospital. During recruitment,cases and controls were told that the purpose of the studywas to complete a battery to assess emotional status.After the study had been described to subjects, informedconsent to participate was obtained. Clinical character-istics were obtained from review of records from theiroutpatient neurological care, including Hoehn and Yahrstage.17 Patients were administered neuropsychologicaltests during “on-time.” All neuropsychological evalua-tions were performed by the same researcher (Y.M.)using the following tests:

A. The STAXI-2 is a valid instrument to record angertrait and anger expression. The Spanish adaptationof the STAXI-2 has been validated and includes 49items (range 0–196), and it is organized into sixscales (including five subscales) and an anger ex-pression index that provides an overall measure oftotal anger expression.13,14 The STAXI-2 scales arelisted below:1. State anger (including the three subscales feeling

angry, feel like expressing anger verbally, andfeel like expressing anger physically). This scaleassesses currently anger as an emotional state.

2. Trait anger (including the two subscales angrytemperament and angry reaction). This scalemeasures how often angry feelings are usuallyexperienced.

3. Anger expression-out. This scale measures ex-pression of anger toward other individuals orobjects in the environment.

4. Anger expression-in. This scale assesses theholding in or suppression of angry feelings.

5. Anger control-out. This scale assesses the controlof angry feelings by preventing the expression ofanger toward other individuals or objects in theenvironment.

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6. Anger control-in. This scale assesses the controlof angry feelings by calming down or cooling off(anger control-in).

7. Anger expression index. This index comes fromthe following formula: (anger expression-out �anger expression-in) � (anger control-out � an-ger control-in) � 36.

B. The Tridimensional Depression Questionnaire(TDQ) (Cuestionario Tridimensional de Depresion[in Spanish]) is a validated 34-item instrument thatassesses cognitive, physiologic, and motor aspectsof depression. This instrument was validated in 332subjects who were ascertained both from the generalpopulation and psychiatric clinics. The mean age ofthose 332 subjects was 33.2 � 12.3 (ranging from18 to 78) years.18 The TDQ has not been appliedpreviously to a group of patients with PD. Each itemwas rated from 0 to 4 and the total score wasobtained by summing each of the 34 items. Higherscores indicate higher levels of depression (rangefrom 0 to 136).18

Data Analysis and Sample Size

Statistical analyses were performed in SPSS Version13.0 (SPSS, Chicago, IL). All tests were two sided, andsignificance was accepted at the 5% level (� � 0.05).The Chi-square (�2) test was used to analyze categoricalvariables. Using a Kolmogorov-Smirnov test, we deter-mined that age, disease duration, TDQ score, andSTAXI-2 scores were not normally distributed (Kolmog-orov-Smirnov tests for all items, P � 0.05). Therefore,although mean and median values were reported, case-control differences were compared using a nonparamet-ric (Mann-Whitney U) test. Correlation analysis wasperformed by Spearman rank correlation. To assess dif-ferences between PD patients and controls in STAXI-2scores while adjusting for age, gender, and depressivesymptoms, linear regression analysis were performed in

which the outcome variables were each one of theSTAXI-2 scores.

The targeted sample size (125–130 participants ineach group) had 93.8 to 94.6% power to detect as little asa 15% difference in anger expression index betweenpatients and controls (assuming � � 0.05).

RESULTS

Of the 152 eligible patients with PD, 13 (8.6%) wereexcluded because they were demented and 13 (8.6%)refused. None were excluded because they were institu-tionalized or had major acute comorbidities. The 26nonparticipants were younger than the 126 participants(median age � 63 years vs. 69 years, Mann-Whitney Utest, P � 0.03). However, there was no gender difference(�2 � 0.13, P � 0.83). Of the 133 eligible controls,seven (5.3%) were excluded because of dementia andnone refused. These seven subjects were marginallyolder than the 126 controls who participated (medianage � 74 years vs. 68 years, Mann-Whitney U test, P �0.09) but there was no gender difference (�2 � 0.13, P �1.0). The final study sample consisted of 126 patientswith PD and 126 controls who were frequency-matchedby age and gender. The patients with PD and controlswere similar in age and gender, although patients withPD had more depressive symptoms (Table 1). Amongcontrols, STAXI-2 scores correlated with the TDQ score(with only one exception, all Spearman’s correlationcoefficients �0.19 and P values �0.05). Among patientswith PD, these correlations were less robust (seven of 12correlation coefficients had P values �0.05).

Table 2 presents the mean and median STAXI-2scores. Overall, patients with PD had significantly lowerscores on intensity (state anger) anger than did controls.Patients with PD tended to repress anger toward otherindividuals or objects in the environment (lower angerexpression-out score), hold in or suppress angry feelings(higher anger expression-in score), control angry feelings

TABLE 1. Comparison of demographic and clinical characteristics of PD patients withdepressive symptoms vs. controls

PD patients (N � 126) Controls (N � 126) P value

Age in years 67.7 � 8.9 (69) 67.1 � 9.6 (68) 0.66a

Gender (female) 63 (50%) 63 (50%) 1.00b

Hoehn and Yahr stage Stage I � 3 Not applicableStage II � 64Stage III � 47Stage IV � 12

Disease duration (yr) 6.6 � 5.2 (5) Not applicableTridimensional depression questionnaire 52.8 � 22.5 32.4 � 17.7 �0.001a

Results are means � SD, and (medians).aMann-Whitney U test.b�2 test.

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by preventing the expression of anger toward other in-dividuals or objects in the environment (higher angercontrol-out score), and control suppressed angry feelingsby calming down or cooling off (higher anger control-inscores) when compared with the control group. Patientswith PD also had lower anger expression index scoresthan did controls.

In a series of linear regression analyses that adjustedfor age, gender, and depressive symptoms, diagnosis(PD patient vs. control) remained significantly associ-ated (P � 0.01) with each one of the STAXI-2 scalescores (dependent variables), except the anger expres-sion-in scale, for which the association was marginal(P � 0.07).

Although we did not assess use of antidepressant med-ications, in an analysis in which we excluded all partic-ipants in the highest quartile of TDQ score, (i.e., thoseparticipants most likely to be using antidepressant med-ications), the differences in STAXI-2 scores between PDpatients and controls remained robust (11 of 12 P values�0.01). In an additional analysis in which we excludedall participants in the highest tertile of TDQ score, thedifferences in STAXI-2 scores between patients with PDand controls also remained robust (11 of 12 P values�0.05).

In patients with PD, the STAXI-2 scale scores did not,in general, correlate with Hoehn and Yahr stage or dis-ease duration. There were only two exceptions. Therewas a correlation between the feel like expressing angerphysically subscale score and the Hoehn and Yahr scale(rS � 0.25, P � 0.004); and between the feel likeexpressing anger verbally subscale and the disease dura-tion (rS � 0.18, P � 0.05).

DISCUSSION

Nonmotor manifestations, including cognitive impair-ment, dementia, depression, apathy, and psychosis are

common in PD.19 Likewise, studies suggest that PD isassociated with a particular group of personality charac-teristics. With relative uniformity, patients with PD havebeen described as industrious, rigidly moral, stoic, seri-ous, and nonimpulsive.20,21

We used the STAXI-2 to study anger in patients withPD and controls. Patients with PD showed lower levelsof external expression of anger and higher levels ofinternal and external control of anger. Overall, the levelof anger in patients with PD was low compared withnormal controls. Our results demonstrate that the inten-sity and frequency of anger as well as angry feelings andthe verbal expressions of anger are lower in PD than ina matched control group. These results remained signif-icant after controlling for age, gender and depressivesymptoms, indicating that these potential confoundersdid not explain the observed case-control differences.

Overall, STAXI-2 scores did not correlate with theHoehn and Yahr stage or with disease duration, suggest-ing that the personality profile we observed could be amanifestation of the underlying disease, independent ofdisease duration or motor severity. Prospective studies ofat-risk individuals could further address whetherSTAXI-2 scores differ before the onset of disease. Also,family studies could be used to look for endophenotypicdifferences in this trait.

The biological bases of anger are still unknown. Theneuroanatomic substrates of anger and aggressive behav-ior have been studied by positron emission tomography,transcranial magnetic stimulation, and functional mag-netic resonance imaging.22-24 The cortical regions in-volved in the control and expression of anger are medial-frontal cortex, left inferior frontal and left temporal poleregions, right posterior temporal/parietal and right supe-rior frontal cortex, and subcortical structures like basalganglia and amygdala.22-24 Serotonin is involved in the

TABLE 2. STAXI-2 scores in PD patients with depressive symptoms vs. controls

Scales PD patients (N � 126) Controls (N � 126) P value*

State anger 15.8 � 3.1 (15) 17.9 � 5.3 (15) �0.001Feeling angry 5.4 � 1.4 (5) 6.5 � 2.8 (5) �0.001Feel like expressing anger verbally 5.3 � 1.4 (5) 6.1 � 2.3 (5) �0.001Feel like expressing anger physically 5.1 � 0.8 (5) 5.3 � 1.2 (5) 0.04

Trait anger 19.2 � 5.3 (18) 20.7 � 6.0 (20) 0.05Angry temperament 7.4 � 2.7 (6.5) 8.8 � 3.5 (8) 0.001Angry reaction 11.8 � 3.5 (12) 11.9 � 3.6 (11) 0.99

Anger expression-out 9.0 � 2.5 (9) 10.5 � 3.0 (10) �0.001Anger expression-in 14.0 � 3.4 (14) 12.2 � 3.2 (12) �0.001Anger control-out 18.6 � 5.0 (20) 16.1 � 5.0 (17) �0.001Anger control-in 14.3 � 4.7 (14) 13.0 � 4.5 (12) 0.02Anger expression index 26.1 � 8.8 (26) 29.6 � 9.4 (29.5) 0.003

Results are means � SD, and (medians).*Mann-Whitney U test.

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modulation of anger and aggressive behavior.8 Somestudies suggest that depressed patients with anger attackshave a greater central serotonergic dysregulation thandepressed patients without such attacks.9,10 In line withthis, a polymorphism of the gene coding for tryptophanhydroxylase, the rate limiting enzyme in serotonin bio-synthesis, was found to be associated with anger-relatedtraits of personality.11 Patients with PD have an impair-ment of serotonin metabolism.12 We hypothesize thatserotonergic dysregulation may play a role in the abnor-malities in anger experience and control observed inpatients with PD.

A potential limitation of this study is that we cannot becertain that the nonresponders (refusals) were similar interms of anger compared with the patients with PD whochose to participate. In addition, while we frequency-matched patients and controls based on age and gender,we were not able to adjust for other potential unmeasuredconfounders. Another limitation is that we did not assessuse of antidepressant medications. The evidence for theeffects of antidepressant medications on anger comesfrom a wide range of sources but there are few controlledtrials or experimental studies.25 Current findings point todecreases in negative mood and anger attacks and posi-tive changes in personality traits after antidepressanttreatment.25 However, in analyses in which we excludedall participants in the highest quartile (and then in thehighest tertile) of TDQ scores, (i.e., those participantsmost likely to be using antidepressant medications), thedifferences in STAXI-2 scores between patients with PDand controls remained robust. Finally, while we did notassess the use of neuroleptic medications, investigatorswere careful to exclude individuals with visual halluci-nations or psychosis, making it unlikely that very manyof our study subjects was using these medications.

In conclusion, patients with PD showed lower levelsof external expression of anger and higher levels ofcontrol of anger when compared with controls of thesame age and gender. Our results seem to demonstrateanother dimension to the stoic personality trait seen inPD. Longitudinal studies of anger in PD are needed tocharacterize the stability and evolution of this personalitytrait within the natural history of the disease process.

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